Abstracts

Rationale: Lethal neonatal rigidity and multifocal seizure syndrome is a severe phenotype characterized by intractable seizures, hypertonia, autonomic instability, and early death and is associated with mutations in BRAT-1, a gene which encodes BRCA1-associated ATM activator 1 protein thought to play a role in the DNA damage response pathway. Even within families, this syndrome can present across a range in phenotypic severity. Here we review two brothers both found to be compound heterozygous for the same pathogenic variant frameshift mutation c.2125_2128delTTTG (p.Phe709Thrfs*17) in the BRAT-1 gene.

Methods: Patient 1 is now a 22-month-old male who initially presented with focal seizures at 23 days of life; neurologic exam at presentation was significant for microcephaly, dysmorphic features, hyperreflexia, and generalized hypertonia. Seizures progressively worsened over time increasing in frequency and becoming increasingly refractory to multiple AEDs; approximately 2 months after initial presentation, seizures became associated with autonomic instability eventually leading to respiratory failure and malnutrition requiring tracheostomy and gastrostomy tube placement at 4 months of age. Developmentally, Patient 1 was noted to demonstrate a social smile, track across midline, and grasp objects however eventually development plateaued then underwent significant regression to total loss of all skills. Patient 2 is the younger brother of Patient 1 and is now an 8-month-old male who initially presented earlier in comparison to Patient 1 with focal seizures on day of life 1; neurologic exam at presentation was also significant for microcephaly and dysmorphic features however was remarkable for greater degree of both visual impairment (no spontaneous eye opening or blink to threat) and hypertonia/spasticity (multiple contractures) compared to Patient 1. Seizures were more frequent, more refractory, and associated with earlier autonomic instability subsequently requiring tracheostomy and gastrostomy placement at a younger age of 1 month. Patient 2 did not attain any developmental milestones.

Results: Patient 2 seems to demonstrate a more severe clinical phenotype than Patient 1 in a number of aspects including: age of presentation, severity of neurologic exam features, degree of seizure intractability and associated electrographic characteristics, age of procedural intervention as related to tracheostomy/gastrostomy dependence, and developmental trajectory.

Conclusions: Retrospective review of these two cases brings to light the intra-familial phenotypic heterogeneity that may exist when it comes to Lethal neonatal rigidity and multifocal seizure syndrome, even when caused by an identical variant mutation at the biochemical protein-encoding level. Furthermore, review of the literature reveals the wide clinical spectrum that exists within all BRAT-1 associated disorders. As genetic testing modalities are increasingly utilized in the diagnosis of these conditions, further studies on genotype-phenotype correlations could prove valuable in earlier and more accurate prognostication, therefore potentially allowing for more informed and compassionate decision-making by caregivers and clinicians.

Funding: Please list any funding that was received in support of this abstract.: None.